The identification of autoantigens in atherosclerotic plaques has prompted investigation of the antibody-mediated pathogenesis of atherosclerotic cardiovascular disease (ASCVD). One target of IgG antibody induction in ASCVD patients is apolipoprotein A-I (ApoA-I), the major protein of high density lipoprotein (HDL). Although anti- ApoA-I antibodies have been identified in mice and human subjects, their role has not been elucidated. The PI has identified immune complexes formed between ApoA-I and IgG (ApoA-I/IgG IC) that exhibit anti-inflammatory characteristics and associate with decreased CVD risk. Continued evaluation of ApoA-I/IgG ICs will improve our understanding of this component of the immune responses associated with ASCVD. The overall goal of this project is to determine the role of ApoA-I/IgG ICs and elucidate their functional impact in ASCVD. To achieve this goal, we will characterize the molecular components of ApoA-I/IgG ICs in mouse and patient sera samples and correlate these factors with cellular interactions, functional outcomes and disease progression. The hypothesis is that ApoA-I/IgG ICs exhibit anti-inflammatory effects mediated through the inhibitory Fc-receptor depending on antibody characteristics (i.e. epitope specificity, subclass), and these effects are capable of suppressing inflammation and disease. The rationale for this proposed research is that understanding one component of the humoral immune response associated with ASCVD will lead to a better understanding of the underlying mechanisms and improve patient outcomes. Encouraged by strong preliminary data, this hypothesis will be tested through two specific aims: 1) Elucidate the molecular components and functional implications of ApoA-I/IgG ICs using cultured cells and mouse models of atherosclerosis; and 2) Determine the characteristics and anti-inflammatory activity of ApoA-I/IgG ICs from human plasma and delineate the association among ApoA- I/IgG ICs and ASCVD in a large community-based cohort. Aim 1 will employ novel immunomodulation strategies, developed in Dr. Venditto's laboratory, to achieve epitope-specific immune modulation of antibody responses in mice to elucidate antibody/epitope function and the role in atherosclerosis progression. Aim 2 will employ sera from human subjects to characterize antibody/epitope function and evaluate the association between ApoA-I/IgG ICs and disease progression in the Multi-Ethnic Study of Atherosclerosis (MESA). The approach is innovative due to the utilization of in vivo immunomodulation approaches to alter ApoA-I/IgG IC profiles, and our approach focused on obtaining detailed ApoA-I/IgG IC profiles in patients for association studies with disease. The proposed research is significant as the outcomes of this research will improve our understanding of antibody- mediated immune responses to ApoA-I to elucidate the role of antibodies on ASCVD progression. Detailed characterizations of the prefinalantigen, epitope specificity, antibody subclass and receptor engagement will enhance our understanding of ASCVD to guide therapeutic development and future efforts to improve risk stratification procedures to decrease the burden of ASCVD in patients.